Improvements in medical interventions and living conditions have dramatically increased the average human lifespan over the last century. As a result, emotional and cognitive fitness has become a major determinant, and unmet challenge, to the quality of life during old age. Indeed, if successful aging is achievable, for numerous individuals, low mood is too often an early symptom and significant contributor to the downward spiral of aging, which includes further cognitive and motor declines. Low mood is also observed in presymptomatic stages of neurodegenerative disorders, together suggesting that mood regulation may be selectively vulnerable at the vigor-to-frailty transition. However, this hypothesis has been difficult to test, as correlations between molecular changes and functional declines are logistically complex to assess in elderly individuals, and, since means to identify individuals at higher biological risk are not available. Here, we propose to identify genetic modulators that associate with both biological and functional aging, by performing parallel postmortem and in vivo studies. Our assay for biological aging is based on the fact that brain aging associates with robust molecular, cellular and structural changes, for which we have identified a specific set of genes with age-dependent expression changes. This molecular signature of aging contains many neuropsychiatric and neurodegenerative disease-related genes, which are affected in disease-promoting directions, suggesting that aging may promote aspects of diseases. Notably, we show that molecular age - defined herein as the age that is predicted by the gene expression profile in that individual - can deviate from chronological age. For instance, individuals carrying a DNA variant in a putative longevity gene (Sirtuin 5) display older molecular ages, potentially through accelerated age-dependent declines in mitochondrial-related gene transcripts. Thus, we hypothesize that subjects carrying risk alleles associated with older brain molecular age will display higher incidence of mood and other low function symptoms, and conversely that subjects carrying protective alleles may experience greater successful aging. To test this hypothesis, we will systematically identify genetic variants associated with older or younger brain molecular ages in postmortem individuals (n~300) (Aim 1). We will then assess the extent to which the presence of these identified risk or protective genetic factors predicts corresponding functional outcomes in vivo in elderly individuals, as manifested by mood, cognitive and motor age-dependent changes in subjects from two epidemiological studies of aging: the Cardiovascular Health (n=5,888) and Health Aging and Body Composition (n=3,075) studies (Aim 2). At the end of this study, we will have achieved (i) the identification of robust genetic markers for biological and functional aging, and (ii) a more detailed characterization of biological/functional links between mood, cognition and motor functions. This will provide (iii) evidence-based hypotheses to monitor critical functional domains in old age, and (iv) biological leads for rational experimental design to investigate successful aging.